There are strong biologic and preclinical rationales for the development of therapeutic cancer vaccines; however, the clinical translation of this treatment strategy has been challenging. It is now understood that many previous clinical trials of cancer vaccines used target antigens or vaccine designs that inherently lacked sufficient immunogenicity to induce clinical responses. Despite the historical track record, breakthrough advances in cancer immunobiology and vaccine technologies have supported continued interest in therapeutic cancer vaccinations, with the hope that next-generation vaccine strategies will enable patients with cancer to develop long-lasting anti-tumor immunity. There has been substantial progress identifying antigens and vaccine vectors that lead to strong and broad T cell responses, tailoring vaccine designs to achieve optimal antigen presentation, and finding combination partners employing complementary mechanisms of action (e.g., checkpoint inhibitors) to overcome the diverse methods cancer cells use to evade and suppress the immune system. Results from randomized, phase 3 studies testing therapeutic cancer vaccines based on these advances are eagerly awaited. Here, we summarize the successes and failures in the clinical development of cancer vaccines, address how this historical experience and advances in science and technology have shaped efforts to improve vaccines, and offer a clinical perspective on the future role of vaccine therapies for cancer.

Purpose: Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T-cell infiltration of tumors include vaccines targeting established oncogenic drivers such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2).Patients and Methods: In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and antitumor function were evaluated. We tested VRP-HER2 in a phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of 3 doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy.Results: Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was 1 partial response and 2 patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n = 4) and 32.7 months in cohort 2 (n = 18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS.Conclusions: VRP-HER2 increased HER2-specific memory CD8 T cells and had antitumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T-cell activity by combining with anti-PD-1.

Expression of human epidermal growth factor family member 3 (HER3), a critical heterodimerization partner with EGFR and HER2, promotes more aggressive biology in breast and other epithelial malignancies. As such, inhibiting HER3 could have broad applicability to the treatment of EGFR- and HER2-driven tumors. Although lack of a functional kinase domain limits the use of receptor tyrosine kinase inhibitors, HER3 contains antigenic targets for T cells and antibodies. Using novel human HER3 transgenic mouse models of breast cancer, we demonstrate that immunization with recombinant adenoviral vectors encoding full length human HER3 (Ad-HER3-FL) induces HER3-specific T cells and antibodies, alters the T cell infiltrate in tumors, and influences responses to immune checkpoint inhibitions. Both preventative and therapeutic Ad-HER3-FL immunization delayed tumor growth but were associated with both intratumoral PD-1 expressing CD8⁺ T cells and regulatory CD4⁺ T cell infiltrates. Immune checkpoint inhibition with either anti-PD-1 or anti-PD-L1 antibodies increased intratumoral CD8⁺ T cell infiltration and eliminated tumor following preventive vaccination with Ad-HER3-FL vaccine. The combination of dual PD-1/PD-L1 and CTLA4 blockade slowed the growth of tumor in response to Ad-HER3-FL in the therapeutic model. We conclude that HER3-targeting vaccines activate HER3-specific T cells and induce anti-HER3 specific antibodies, which alters the intratumoral T cell infiltrate and responses to immune checkpoint inhibition.

Photodynamic therapy (PDT) ablates malignancies by applying focused near-infrared (nIR) light onto a lesion of interest after systemic administration of a photosensitizer (PS); however, the accumulation of existing PS is not tumor-exclusive. We developed a tumor-localizing strategy for PDT, exploiting the high expression of heat shock protein 90 (Hsp90) in cancer cells to retain high concentrations of PS by tethering a small molecule Hsp90 inhibitor to a PS (verteporfin, VP) to create an Hsp90-targeted PS (HS201). HS201 accumulates to a greater extent than VP in breast cancer cells both in vitro and in vivo, resulting in increased treatment efficacy of HS201-PDT in various human breast cancer xenografts regardless of molecular and clinical subtypes. The therapeutic index achieved with Hsp90-targeted PDT would permit treatment not only of localized tumors, but also more diffusely infiltrating processes such as inflammatory breast cancer.

Background/Objectives: Regulatory T cells (Treg) suppress immunity in the tumor microenvironment, are linked to poor prognosis across breast cancer subtypes, and suppress the cytolytic function of cytotoxic CD8+ T cells. Denileukin diftitox, a diphtheria toxin (DT)/IL-2 fusion protein, targets and depletes Tregs. This Phase II study aimed to assess the safety of denileukin diftitox and its effect on Tregs and tumor growth in patients with advanced breast cancer. Methods: This single-arm Phase II study of denileukin diftitox enrolled patients with refractory stage IV breast cancer. Patients received denileukin diftitox 18 mcg/kg/day IV for Days 1–5 every 21 days for up to six cycles. Toxicity was assessed using CTCAE v3.0 and tumor response was evaluated per RECIST criteria. Blood samples were collected to analyze Tregs by flow cytometry and anti-DT antibodies by ELISA. Results: Fifteen patients with stage IV breast cancer were enrolled. Four patients completed all planned denileukin diftitox infusions and achieved stable disease (27%, 95% CI [0.08, 0.55]). Two patients (13%) discontinued due to toxicity, and nine patients (60%) discontinued due to progressive disease. Eleven patients experienced at least one grade 3 or 4 adverse event. Although there was a general reduction in peripheral blood Tregs, the difference in CD4+CD25+FOXP3+ Tregs levels post-treatment was not statistically significant (p = 0.10). Six patients (40%) achieved $\ge$25% reductions in Tregs. A significant increase in anti-DT IgG antibodies was observed post-treatment (p < 0.005). Conclusions: Denileukin diftitox demonstrated moderate toxicity in this advanced breast cancer cohort. Denileukin diftitox modulated regulatory T cells. However, the majority of patients experienced disease progression in the study.

TPS592 Background: Adoptive cellular therapies can lead to durable responses in treatment refractory leukemias and lymphomas; however, these approaches are still in early stage development for metastatic solid tumors. FH-MagIC TCR-T is an autologous CD8+ and CD4+ T cell product transduced with a transgenic T cell receptor (TCR) targeting MAGE-A1. MAGE-A proteins are classified within the “testis restricted” cancer testis antigens and are broadly expressed in a wide range of malignancies, including urothelial carcinomas, triple negative breast cancers (TNBCs) and non-small cell lung cancers (NSCLCs). Importantly, MAGE-A1 is undetectable in most normal tissues exclusive of the immune privileged testes, thereby making MAGE-A1 an ideal target for T cell immunotherapy approaches. Of note, FH-MagIC TCR-T is specific to the Class I HLA A*02:01-restricted MAGE-A1 epitope. Based on preclinical studies testing FH-MagIC-T in MAGE-A1 expressing tumor models, we have launched a Phase I/II study evaluating this autologous transgenic TCR therapy. Methods: This is a Phase I/II study testing FH-MagIC TCR-T cells in patients with metastatic urothelial carcinoma, TNBC or NSCLC. Eligible patients must have HLA type HLA-A*02:01 and demonstrate expression of MAGE-A1 on archival tumor tissue (≥1+ by immunohistochemistry). Patients must have been offered or received: i) anti-PD(L)1 therapy; ii) enfortumab vedotin (urothelial carcinoma patients); and iii) FDA-approved targeted therapies (e.g. NSCLC patients with actionable mutations in EGFR, ROS1, etc.). For each dose level (DL) in the Phase 1 portion, 1 patient will be treated without lymphodepletion (LD). If no dose limiting toxicities (DLT) are observed, the next 3 patients will receive LD with cyclophosphamide 300mg/m² and fludarabine 30mg/m² IV days -4 to -2 before T cell infusion. The first 4 patients will be treated at DL1: 1 x 10⁹ cells. If no DLTs are observed, the next 4 patients will be treated at DL2: 5 x 10⁹ cells. Otherwise, if a DLT is observed at DL1, the next 4 patients will be treated at DL-1: 5 x 10⁸ cells. The Phase 2 portion of the trial will test FH-MagIC-TCR T cell product at the RP2D with the addition of standard of care anti-PD(L)1 therapy. Primary objectives are to assess safety (Phase 1) and radiographic response rate (Phase 2) per RECIST v1.1. Secondary objectives will evaluate progression free survival, overall survival, persistence of transgenic T cells in peripheral blood and migration into tumor tissue. For the Phase 2 portion, we assume a 5% null response rate (H0). If the true response rate with TCR-transduced cells is 25% (H1), 15 patients will yield 84% power at a one-sided alpha =.05. Clinical trial information: NCT04639245.